A number of treatments involving the administration of non-steroidal anti-inflammatory drugs (NSAIDs) are currently recommended for pain relief. The administration of NSAIDs has been shown to display pain alleviating properties. However, treatment with NSAIDs has known disadvantages, including unwanted side effects such as irritation of the gastrointestinal tract and kidney and liver toxicity. Moreover, NSAIDs cannot achieve adequate pain alleviation even at their maximum therapeutically approved doses in some pain states.
Nerve growth factor (NGF) was the first neurotrophin identified, and its role in the development and survival of both peripheral and central neurons has been well characterized. NGF has been shown to be a critical survival and maintenance factor in the development of peripheral sympathetic and embryonic sensory neurons and of basal forebrain cholinergic neurons (Smeyne, et al., Nature 368:246-249 (1994); Crowley, et al., Cell 76:1001-1011 (1994)). NGF upregulates expression of neuropeptides in sensory neurons (Lindsay, et al., Nature 337:362-364 (1989)) and its activity is mediated through two different membrane-bound receptors, the TrkA tyrosine kinase receptor and the p75 receptor, which is structurally related to other members of the tumor necrosis factor receptor family (Chao, et al., Science 232:518-521 (1986)).
In addition to its effects in the nervous system, NGF has been increasingly implicated in processes outside of the nervous system. For example, exogenously administered NGF has been shown to enhance vascular permeability (Often, et al., Eur. J. Pharmacol. 106:199-201 (1984)), enhance T- and B-cell immune responses (Often, et al., Proc. Natl. Acad. Sci. U.S.A. 86:10059-10063 (1989)), induce lymphocyte differentiation and mast cell proliferation and cause the release of soluble biological signals from mast cells (Matsuda, et al., Proc. Natl. Acad. Sci. U.S.A. 85:6508-6512 (1988); Pearce, et al., J. Physiol. 372:379-393 (1986); Bischoff, et al., Blood 79:2662-2669 (1992); Horigome, et al., J. Biol. Chem. 268:14881-14887 (1993)).
NGF is produced by a number of cell types including mast cells (Leon, et al., Proc. Natl. Acad. Sci. U.S.A. 91:3739-3743 (1994)), B-lymphocytes (Torcia, et al., Cell 85:345-356 (1996), keratinocytes (Di Marco, et al., J. Biol. Chem. 268:22838-22846)), smooth muscle cells (Ueyama, et al., J. Hypertens. 11:1061-1065 (1993)), fibroblasts (Lindholm, et al., Eur. J. Neurosci. 2:795-801 (1990)), bronchial epithelial cells (Kassel, et al., Clin, Exp. Allergy 31:1432-40 (2001)), renal mesangial cells (Steiner, et al., Am. J. Physiol. 261:F792-798 (1991)) and skeletal muscle myotubes (Schwartz, et al., J Photochem. Photobiol. B 66:195-200 (2002)). NGF receptors have been found on a variety of cell types outside of the nervous system. For example, TrkA has been found on human monocytes, T- and B-lymphocytes and mast cells.
An association between increased NGF levels and a variety of inflammatory conditions has been observed in human patients as well as in several animal models. These include systemic lupus erythematosus (Bracci-Laudiero, et al., Neuroreport 4:563-565 (1993)), multiple sclerosis (Bracci-Laudiero, et al., Neurosci. Lett. 147:9-12 (1992)), psoriasis (Raychaudhuri, et al., Acta Derm. l'enereol. 78:84-86 (1998)), arthritis (Falcimi, et al., Ann. Rheum. Dis. 55:745-748 (1996)), interstitial cystitis (Okragly, et al., J. Urology 161:438-441 (1999)) and asthma (Braun, et al., Eur. J Immunol. 28:3240-3251 (1998)).
Consistently, an elevated level of NGF in peripheral tissues is associated with hyperalgesia and inflammation and has been observed in a number of forms of arthritis. The synovium of patients affected by rheumatoid arthritis expresses high levels of NGF while in non-inflamed synovium NGF has been reported to be undetectable (Aloe, et al., Arch. Rheum. 35:351-355 (1992)). Similar results were seen in rats with experimentally induced rheumatoid arthritis (Aloe, et al., Clin. Exp. Rheumatol. 10:203-204 (1992)). Elevated levels of NGF have been reported in transgenic arthritic mice along with an increase in the number of mast cells. (Aloe, et al., Int. J. Tissue Reactions-Exp. Clin. Aspects 15:139-143 (1993)).
There are two general categories of medication for the treatment of pain, each acting via different mechanisms and having differing effects, and both having disadvantages. The first category includes the nonsteroidal anti-inflammatory drugs (NSAIDs) which are used to treat mild pain, but whose therapeutic use is limited by undesirable gastrointestinal effects such as gastric erosion, formation of peptic ulcer or inflammation of the duodenum and of the colon and renal toxicity with prolonged use. The second category includes the opioid analgesics, such as morphine, which are used to treat moderate to severe pain but whose therapeutic use is limited because of undesirable effects such as constipation, nausea and vomiting, respiratory depression, mental clouding, renal colic, tolerance to prolonged use and risk of addiction.
It is evident that there is a need for an improved pain treatment that provides an improved therapeutic benefit (e.g., reduced severity and/or frequency of pain) and/or reduces the incidence of unwanted side effects caused by many of the current regimens.
All references cited herein, including patent applications and publications, are incorporated by reference in their entirety.
Deposit Information
Applicants have deposited the polynucleotides encoding the E3 heavy chain and the E3 light chain variable region of the antibody designated as E3 herein with the American Type Culture Collection (ATCC) Manassas, Va. 20110-2209 U.S.A. As noted in the foregoing, the E3 antibody light chain variable region was deposited on Jan. 8, 2003 and was assigned ATCC Deposit No, PTA4893 (Vector Eb.911.3E) and ATCC Deposit No. PTA-4894 (Vector Eb.pur.911.3E), and the E3 antibody heavy chain variable region was deposited on Jan. 8, 2003 and was assigned ATCC Deposit No. PTA-4895 (Vector Db.911.3E). These deposits were made under the provisions of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purpose of Patent Procedure and the Regulations thereunder (Budapest Treaty). These deposits will be maintained in the ATCC depository for a term of at least thirty (30) years and at least five (5) years after the most recent request for the furnishing of a sample of the deposited material or for the effective life of the patent, whichever is longer and will be replaced if the deposits become non-viable during that period.
Applicants have deposited the polynucleotides encoding the E3 heavy chain and the E3 light chain variable region of the antibody designated as E3 herein with the American Type Culture Collection (ATCC) Manassas, Va. 20110-2209 U.S.A. As noted in the foregoing, the E3 antibody light chain variable region was deposited on Jan. 8, 2003 and was assigned ATCC Deposit No. PTA-4893 (Vector Eb.911.3E) and ATCC Deposit No. PTA-4894 (Vector Eb.pur.911.3E), and the E3 antibody heavy chain variable region was deposited on Jan. 8, 2003 and was assigned ATCC Deposit No. PTA-4895 (Vector Db.911.3E). These deposits were made under the provisions of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purpose of Patent Procedure and the Regulations thereunder (Budapest Treaty). These deposits will be maintained in the ATCC depository for a term of at least thirty (30) years and at least five (5) years after the most recent request for furnishing of a sample of the deposited material or for the effective life of the patent, whichever is longer, and will be replaced if the deposits become non-viable during that period.